GAIN-(C): Efficacy and safety analysis of imgatuzumab (GA201), a novel dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with FOLFIRI compared to cetuximab plus FOLFIRI in second-line KRAS exon 2 wild type (e2WT) or with FOLFIRI alone in mutated (e2MT) metastatic colorectal cancer (mCRC)

Background: Imgatuzumab, a humanized engineered IgG1 anti‐Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, showed promising clinical activity in a phase I trial including KRAS MT mCRC. This multicenter phase II study (NCT01326000 ) aimed to compare the combination of imgatuzumab with FOLFIRI to cetuximab plus FOLFIRI or FOLFIRI alone as second‐line treatment in patients with both KRAS e2WT or e2MT mCRC. Methods: Patients underwent a mandatory fresh tumor biopsy at screening to assess KRAS exon 2 status. KRAS e2WT patients were randomized (1:1) to treatment groups 1 or 2 to receive imgatuzumab (1,400 mg IV on day 1 and 8 then q2‐weekly) or cetuximab (400 mg/m2 IV on day 1 followed by 250 mg/m2 IV q‐weekly) respectively plus FOLFIRI (standard IV chemotherapy). KRAS e2MT patients were randomized to groups 3 and 4 to receive imgatuzumab plus FOLFIRI or FOLFIRI alone respectively. Patients were stratified by EGFR expression, time to disease progression on first line treatment and prior treatment with bevacizumab. A run‐in phase (n=6/group) was performed to confirm tolerability before recruitment proceeded. Results: 169 patients with an evaluable fresh tumor biopsy were randomized. Median PFS (Investigator reported) was 7.3 months in group 1 versus6.1 in group 2 (HR, 1.13; 95% CI 0.69‐1.86) and 5.2 months in group 3 versus 4.3 in group 4 (HR, 0.94; 95% CI 0.57‐1.54). Adverse events of > grade 3 included rash (42.5%, 9.8%, 31.8%, 0% in groups 1, 2, 3 and 4 respectively), hypomagnesemia (30.0%, 4.9%, 22.7%, 0% respectively) and neutropenia (20.0%, 29.3%, 25.0%, 21.4% respectively). Conclusions: The outcome was negative with respect to the primary efficacy endpoint (PFS) with no benefit seen for the addition of imgatuzumab to FOLFIRI in second‐line in both KRAS e2WT and e2MT populations. We demonstrated that collection of fresh tumor biopsy is feasible in pretreated CRC.